Overdose and abuse of methamphetamine ((+)-METH), (+)-amphetamine ((+)-AMP), or (1)- methylenedioxymethamphetamine ((1)-MDMA) exact significant medical and social costs in the USA and abroad. However, to date, no medications are approved to treat acute and chronic toxicity from these drugs. Medicines that will help transition patients from the emergency department into longer-term treatment programs that promote healthy behavioral change are also needed. The purpose of the proposed research is to produce and complete pre-clinical tests of a new, chimeric monoclonal antibody antagonist (designated ch- mAb4G9) that will bind (+)-METH, (+)-AMP, and (+)-MDMA. Ch-mAb4G9 selectively and quickly binds these target ligands in the blood, reversing the flux of these drugs into the brain and rendering them inactive without altering the function of any catecholamine receptor, thus providing a unique approach for treating drug abuse. The goal of this project is to successfully complete an investigational new drug application (IND) with the indication being treatment of stimulant overdose. Ch-mAb4G9 could be given in the emergency department to initiate treatment by reducing the acute effects of an overdose. It could then be given as part of a behavioral modification program to block pleasurable, reinforcing stimulant effects. Unlike small molecule antagonists, monoclonal antibody (mAb) therapies should not affect normal CNS activity or systemic homeostasis, and they will not interact with psychoactive medications. Furthermore, their intravenous (iv) administration will result in rapid beneficial effects in an overdose. Ch-mAb4G9 could thus have a broad impact, without excluding other treatment options. In the proposed research, mAb4G9, a high affinity anti-(+)-METH mouse mAb that reduces the effects of iv (+)-METH doses in rats, will be produced as a human/mouse chimeric mAb and tested in rats for safety and pre-clinical efficacy in preparation for Food and Drug Administration (FDA)-approved human trials. A transdisciplinary academic/industry team will accomplish the necessary, integrated Specific Aims: 1) establishing a high-yield master cell bank that secretes ch-mAb4G9 and producing the medication for testing;2) extensive testing of ch-mAb4G9 for bioequivalence with the mouse form of the mAb;3) in vitro (human and rat) and in vivo (rat) toxicology testing;and 4) document preparation, quality control, and clinical protocol development necessary for a successful IND application. NIDA funding alone has supported the discoveries and methods development that have brought us to this point. However, this work cannot be reasonably expected to be carried out successfully without GO grant support because these FDA-required studies are expensive, and capital funding for early-stage drug development companies to prepare new drug abuse therapies for human trials is scarce. Nevertheless, this project is ready to be deployed immediately upon funding, and the successful development of this new therapy with FDA validation will leverage the previous work by the investigators to develop the resources needed for a long-term, sustainable program. PUBLIC HEALTH RELEVANCE: We have developed a new medication for treating toxic effects from overdose and long-term use of (+)- methamphetamine, (+)-amphetamine, and (1)methylenedioxymethamphetamine ((1)-MDMA) which has the potential to reduce their devastating behavioral and societal effects, and therefore improve public health. This innovative antibody medication could provide an essential missing component in transitioning the patient from emergency care into long-term programs that promote healthy behavioral changes. This project will produce and perform all testing of a chimeric monoclonal antibody medication necessary to prepare for conducting human clinical trials.